Area Doctor Shatters Area Girl's Dream of Being Taller Than She Is. (A personal genomics parable)

March 15, 1993. Oviedo, FL - A sophomore at OHS who injured the soft tissue in her knee in a freak accident while warming up for the 4 x 100 meter relay at an area track meet on Friday night was told, by her doctor, that she is done growing.

X-rays of Holly Dunsworth's knee--part of routine injury diagnosis and plans for repair--showed that the growth plates in her proximal tibia and distal femur are fused. This indicated to the doctor that Dunsworth has completed growth and has reached her full stature, so he passed this information along to her.

"He said it so cavalierly, too," said Dunsworth. "I spent my whole life wondering how tall I'd grow to be, hoping and wishing I'd grow to be tall enough to really dominate on the basketball court. And my doctor didn't even warn me that he was about to deliver this dream-killing news, and he definitely didn't ask me if I even wanted to hear it in the first place."

x-ray of human knee showing unfused growth plate of still-growing tibia (lower right bone). Source

The news was "even more devastating," said Dunsworth, than learning that her knee injury would most likely require surgical ACL (anterior cruciate ligament) reconstruction, meaning several months of recovery and probably a missed junior year of basketball.

"Sitting out a varsity basketball season just as I'm starting to be noticed by college recruiters is one thing," said Dunsworth, "but learning that I'll probably never be tall enough to play in the NBA or the Olympics is another. What should I dream now? What can I look forward to? I will never dunk. It's over. I wish the doctor would have kept my growth plates to himself."

When asked whether she expected to be much taller than her present 5'7" because she'd seen other girls continue to grow taller at her age, or whether it was because of her freakishly tall parents, Dunsworth said, "Oh no. Girls are pretty much full-sized by sophomore year. And my dad's 5'11" and my mom's 5'8". But I guess I just hoped I'd luck out. And now all that hope is gone, long gone. A big part of me is dead and I don't know how I'll fill this hole with anything good. I just don't know how I'll do it."

***
True story. Fake quotes. Thanks, The Onion, for the inspiring framework. Note that I did not work the word "cavalierly" into my verbal capacity until many many years later. (Fine, it was today.)  

Here's a look at one of the dreams that died that day:

***

If you follow this blog then you know that we talk about personal genomics quite a bit. My parable's not a perfect comparison for many reasons.  Obviously the cessation of growth is not equivalent to the cessation of life (death sentences, being how people can interpret genomic data) or even to the deterioration of health, as with the onset of disease. Further, my complete growth plate fusion was not probabilistic news, like so many of the genetic interpretations that companies like 23andMe provide.

But I thought it was important to share this sort of story where my identity and dreams were wrapped up in my biology and where a doctor delivered news of incidental findings about that biology (which deeply affected my identity and my dreams) without my consent or without even considering my feelings.

I had some rather ignorant notions about biology if I thought I could still grow taller past 16 years of age, especially given my parents' heights, but does it matter if you consider how fundamental those assumptions, however misguided, were to forming my identity? I never even stopped to consider whether I was done growing. It was always a hopeful mystery. Learning from a scientific authority that it was all over was harsh. It's culture, people, and it's not always rational but it's what we do. It's who we are.

On the other hand, culture changes with education. Humans will always have dreams, and I will always have dreams, but maybe my dreams would have been different in high school had I learned to ditch magical thinking in favor of the real evidence staring me in the face. Thanks to family history and to growth patterns of my classmates, it was obvious that I was done growing. I shouldn't have needed the doctor to tell me that! But I did. I needed the education. I needed to be enlightened.

I've been thinking about this story of mine because of what I've been reading about personal genomics and probability lately:

1. What Your Doctor Isn't Telling You About Your DNA. (Time Magazine)
2. John Hawks's recent reflections on things like the Time piece.
3. Razib Khan's reaction to the Time piece
4. Genetics textbook author Ricki Lewis doesn't want to see her genome
5. If you're taking gene-based probabilities as certainties--the hullabaloo over Nate Silver's estimates  demonstrated that many do!--then there's potential for harm from participating in personal genomics.

***

Sure, a big part of the personal genomics dilemma is whether to make people worry about something they cannot prevent at our present level of knowledge (e.g. Huntington's, which 23andMe does not report).

But another big part of the personal genomics dilemma is whether to make people worry over nothing at all (e.g. higher estimated gene-based risk but the condition never ends up presenting).  This is the paradox of probabilistic medical data.  There was no such uncertainty or estimation about my fused growth plates, and since the news wasn't about how I could get sick or die, that's presumably why my doctor did not have to seek my consent to tell me this incidental finding of the radiography.

That I'm done growing is fact. That I have increased risk of breast cancer is fact-ish. It's a fact that I have certain SNPs or alleles or mutations associated with a specific type of breast cancer. That's certain.  Whether those alleles are meaningfully associated with breast cancer isn't. And what having those alleles means for me, Holly Dunsworth, isn't either. My risk for breast cancer might not be as high as 23andMe estimated (or it could be even higher, or it could be  lower). That estimate's not based on any data from my lifestyle and environment. It's only based on my genes in my spit--and only the genes that were genotyped. My report of increased breast cancer risk has got the potential to worry me over nothing. But it could also make me more vigilant so I can catch it early if it does occur.

I'm one of the many out there who wants to know everything about my genome that I can, even if interpreting much of it requires fancy brains to program fancy computers to estimate probabilities. I unlocked my Alzheimer's and Parkinson's reports on 23andMe and if they genotyped for Huntington's I'd have unlocked that too. I'd like to have all the information I can have. I hope risk estimates will improve over time. I'm optimistic like that, but (a) I understand very well that there is so much of our health, our lives, etc that we will never be able to predict no matter how much science learns about the genome and (b)  I have no idea how high a reported disease risk has to be to significantly worry me. Something is bound to kill me. If it's not all the confounders of old age, then hopefully it's molten lava or a black hole or chocolate. What's the big deal? We all die. I'm also pretty comfortable with some level of genetic determinism since genes figure greatly in how bodies work. It's not scary. It is what it is. Actually, it's brilliant. And it's even more amazing that it's a terribly difficult and sometimes impossible system to understand. If it wasn't so complex, all our little variations wouldn't have the wiggle room and the workarounds to function and to function well!

That earth-shattering news about my growth plates? I got over it. And pretty quickly. That hole inside my melodramatic, Holden Caufield-loving teenage heart? It was filled up with other dreams.

I wonder about all those people with life-threatening conditions and a shortened life expectancy. My grandfather was one of them, living some 40 years past his expiration date. I recently met an enchanting 70 year-old woman with a heart condition and an expiration date of 25 years old. She claims that it was her doctor's diagnosis (some might call it a death sentence) that gave her such a wonderful life, inciting her to cherish every moment and seek pleasure in ways that others do not or cannot.

But while deciding whether to see your genome and to receive the disease risk estimates calculated from it, how does anyone know they'll react like my joie-de-vivre'd friend? How does anyone know whether probabilities of disease-risk will be at least not misery-inducing and at best life-enhancing? Could there be a SNP for this charmed outlook on life/death that we could test for before we agree to learn what our disease genes say?

*wink*

And as for the new dreams that filled the empty hole in my soul where all the basketball dreams had died:  Maybe those new dreams were better dreams! I can certainly choose to describe my life in hindsight that way. And I do. They really were much better dreams. Similarly, I can choose to see my increased risk for breast cancer, psoriasis, age-related macular degeneration, rheumatoid arthritis, restless leg syndrome, exfoliation glaucoma, melanoma, esophageal squamous cell carcinoma, and stomach cancer (so says 23andMe) anyway that I choose.

For starters, ever met anyone afflicted with all those problems during their life? Right. That's really telling isn't it? And, of course, understanding even in theory how those risk estimates are made helps a great deal. And so does knowing that most of those conditions are already documented in my family history. And so does knowing that for some known conditions I could have new mutations that are hard to detect, or may never be detected. And so does knowing that those risk estimates don't incorporate my phenotype, lifestyle, or environment. And so does knowing that, just by being alive, my risks for obesity, coronary heart disease, and type 2 diabetes are still higher than my relatively increased risk for any of those aforementioned conditions.

Exercise, eat well, live right. My genes are my genes. And it is what it is. It's what I've got and it's good. Amen, awomen, amonkey.

And if this post wasn't a slam dunk, surely I'll have another shot. Because of how I'm built, I have no choice but to believe that I will.

GWAS, hype and cashing in -- DTC genetic testing

In our opinion, the problems with direct-to-consumer (DTC) genetic testing has never been so accurately described as it is by Murray et al. in the latest issue of Trends in Genetics (well, except maybe when we did it here).

 Among the estimated 480 different traits covered in the collective offerings of current DTC genetic-testing companies there are tests for the creative, musical, linguistic, and shyness ‘genes’, as well as for intelligence, athletic aptitude, and bad behavior.One company promotes a testing package for ‘inborn talent’ as the ‘result of the Human Genome Project’ (http://www.mygeneprofile.com/talent-test.html). Other companies use ‘proprietary technology’ to offer personalized nutritional products based on genetic testing (http://www.ilgenetics.com). Often without citing a single DNA variant or gene, companies promote their products under the protective cloak of legitimate science.

The authors provide a number of examples of tests these companies offer for genetic susceptibility to traits like athletic ability or 'avoidance of error' based on data from small studies or results that haven't been replicated.  They do say that the quality of supporting scientific evidence offered varies by company, with some being at least more formally careful than others to tell their customers that the evidence isn't strong.  But Murray et al. rightly point out that to offer the tests at all, under the guise of scientific authority, is misleading and wrong.

Why are these tests being put on the market at all? Their very offering with the accompanying ‘information’ implies that the test results are meaningful, and thus misrepresents how the scientific community comes to accept conclusions as valid.

They go on to say that scientists publishing new genetic findings have the responsibility to publicly and pre-emptively state that their results are not definitive, and are not for commercial use.  Editorial writers for journals should point out the same thing when they highlight these kinds of results.  The distortion (their word) of science in the way that the DTC companies offer should be countered by "active engagement of the public by scientists in a way that both informs and encourages debate over the social consequences of new scientific findings".

We heartily agree.  Even when a company posts some quality evaluation of studies they cite, as if they're informing the customer, they know very well what the impression of the customer  will be.  If the studies are weak, an honorable company would not do the test (and reduce costs and claims accordingly).

The issue of FDA oversight of these companies has gotten a lot more play than the question of whether they are offering anything of actual value to the consumer, or the extent to which this is just a new version of snake-oil salesmen.  These companies are often, perhaps largely using results from GWAS and other similar kinds of studies, that by now every candid person knows have not delivered nearly the promised goods in regard to clearly causal, reliable, risk-estimable results.

Of course, some alleles can be tested for and have high predictive power, but those can, and often if not usually have, been the purview of legitimate genetic counseling services.  And most people who use the services out of the blue won't have such alleles, or they or their family would already have the condition, if the allele is due to a reliably predictive allele.  If they do, they should already be under the care of a specialist clinic.  And recessive traits involve mates not just individual customers, and are generally much trickier to understand from DNA sequence data.  And a negative DTC result does not mean a clean bill of health, for too many reasons to go into here.

This is all if we're talking disease.  If we're talking designer children and whether to make your kid practice his/her football or violin, who knows?  Or deciding how you should vote  based on your genotype.  What unconstrained kinds of nonsense are afoot!

Of course the companies want to stay in business (is it fair to say 'cash in' while they can?)  but there is probably, for some at least, a more than trivial objective of doing good for customers.  But the overall industry doesn't seem much like a responsible, ethical endeavor.  Some of the scientists involved in the best companies know very well what they are doing. 

At the very least, as in any technical industry in which consumers have no way at all to defend themselves adequately, we need strong evidence-based regulation of this industry.  Otherwise it will cost the health care system enormous amounts of money chasing down false signals, will provide fodder for all sorts of malpractice suits, and in doing so will show that culpably casual acceptance and promotion of GWAS-like studies that promise 'personalized genomic medicine' have been damaging rather than benefiting to public health.  Casual hype is not idle play, and is short-term gain for a few with long term costs for many.

The recent studies claiming that, in a contorted way, a genetic variant determines how you vote, and some of the 'talent' claims of DTC companies that we mentioned above, have more than a little whiff of similarity to the same kinds of claims made, starting with Darwin and through the eugenics movement up to World War II.   Triggered by the 'liberal gene' study, we have promised to expound on that and other fashionable social-behavior genetics and we'll do it, but we've been too busy this week and last.

Even if nobody in the DTC companies has a new eugenics or a new round of social Darwnism in mind, the potential for their hyped promotion of genetic determinism to be used for corporate or government policy, with potential societal abuse, is obvious.  Dismissing DTC as a fad is playing with matches.

Direct-to-consumer genetic testing -- again

An opinion piece published in Science on Oct 8, entitled "Regulating Direct-to-Consumer Personal Genome Testing" calls for the Food and Drug Administration to enact a multi-tiered policy for regulating DTC genetic tests.  The strength of regulation would be determined by the level of risk for a given test, determined by the kinds of decisions test results might lead the consumer to make.  The determination of what kind of earwax you have based on your DNA, for example, would be considered essentially risk free while breast cancer testing might be high risk, since you might decide to have a double mastectomy if the results suggest that your chances are great.  High risk tests would require pre- and post-testing counseling by qualified professionals.

In addition,

All tests should be analytically valid (able to accurately and reliably measure what they say they are measuring), and any clinical claims made about the test must be accurate and substantiated. Safety and effectiveness data should be developed, but for many tests, this should be done through enhanced postmarket surveillance and clinical studies, rather than a more stringent premarket approval process. Premarket assessment would focus on identifying tests with potential for egregious harms (e.g., tests with uncertain validity or utility that could profoundly alter the course of medical treatment) and keeping those tests off the market until further studies show an acceptable risk-benefit ratio.

The idea of regulating these tests for the benefit of the consumer is all well and good, but as we've said before, the idea that regulation is based on ensuring the accuracy of risk prediction is predicated on the assumption that such predication can even be accurate.

Some genetic testing is highly accurate.  That would be prenatal tests for single gene diseases of childhood.  And the field of genetic counseling is successfully based on these kinds of risk assessment.  But that's not what the DTC genetic testing companies are selling.  Earwax genes, may well be harmless recreation but DTC's are primarily selling predictions of the chances you'll get things like type 2 diabetes, or heart disease, or age-related macular degeneration or Parkinson's disease.  These are conditions that have late ages of onset, and are most likely due to a combination of genetic and environmental factors.

And, it turns out that risk estimates for particular genes routinely vary wildly depending on the study, the study population, environmental exposures and other factors.  In addition, risk estimates for specific genes are generally quite low.  That is, they don't raise the risk of disease by very much.

There's another very important point here, too, that nobody wants to hear.  We know from extremely well documented data that risks of most of the relevant diseases (diabetes, cancer, heart disease, etc.) have increased greatly in living memory.  That's environment, not genes!  Even breast cancer risk fluctuates, even for people with the high risk alleles, depending on when a carrier was born.  Genetic effects depend on context.  Yet knowing as we do that the effect of context can change we know that we don't know the future environmental exposures -- and hence the future risks associated with the same genotypes.  Many or most DTC risk estimates are, quite literally, passé.

So, again as we've said before, regulation of what these companies is selling is a legal issue that must be thrashed out, but probably even more important is the epistemological issue of whether what they're selling means anything at all.  It's in nobody's interest -- except the consumers -- to acknowledge, much less deal with this serious issue.

Francis Collins, personalized genomic medicine, and the nature of probabilistic risk

Probability and the weather
Personalized forecasts
People regularly complain about the weather forecast in a way that misunderstands probability.  It's a sensitive subject for Ken, as a one-time meteorologist in a long-ago former life.  If the forecast is for a 30% chance of showers, and it stays dry, it's often viewed as a bad forecast.  You should have played golf after all.  If it rains, it's often viewed as a bad forecast.  Dammit, they ruined your golf outing, by driving you prematurely into the 19th hole bar!

Neither conclusion is right.

One can only really tell whether the forecast was right the next day, by totaling up the area that received rain, or by averaging the fraction of each area that received rain at any given time, or something like that.

The key point is that this is a 'personalized' forecast in the same way that genomic medicine, and Direct to Consumer (DTC) genetic risk estimation are personalized.  For a given genotype, or given golf course, whether it actually rains or not, or whether you get the disease in question, is almost irrelevant to whether the forecast was a good one.

Probability and risk of disease
Personalized genomics
We said on Saturday that Francis Collins reactions to his genotypic diagnosis of being at elevated risk for diabetes were, at his diabetes-free status at age 60, irrelevant to the genotype-testing result.  If the population average risk of diabetes is, say, 10%, that means 10% of the population will get the disease at some point in their lives.  If Francis' genotype-based relative risk is elevated by, say, 20% relative to  the risk of the average Joe, his absolute risk is raised to 12% (and we're exaggerating risks here to make the point, since most of the genotype-based  risks of common diseases add considerably less than 20% of the average lifetime relative risk, and most lifetime risks are less than 10%).

But in fact he doesn't have diabetes.  That says almost nothing about the accuracy or usefulness of his risk estimate.  12% risk means that 88% of people with the same genotype don't get diabetes, and his status is wholly consistent with that (or with his being at the average risk), and says nothing about whether the risk estimate was accurate.  The only risk estimate that should affect his behavior (he reports slimming down etc. in response to the genotype data), is the 'conditional' risk of getting diabetes at some future age, for a white male who has already survived until age 60.  That is probably an unknown value, for many reasons, such as lack of enough data.   Indeed even if the genetic risk estimate is accurate, a person with his genotype could, if diabetes-free at age 60, actually be at lower than average risk from his age onward.  Why?  Because the bulk of those who were born with the same genotype might already have gotten diabetes at a younger age: earlier onset is a typical way that elevated-risk genotypes work.

The issues are subtle, and just like weather forecasts, easy to misunderstand.  Another reason people should shun DTC services, and just adopt health lifestyles to the extent they can.

More profoundly, if Dr Collins is at our hypothetical 20%  relative risk, that means that the average person with his detected genotype is at 20% increased risk, but does not mean that everyone with that genotype is!  For example, those with the genotype who eat too much McFastfood may be at a 90% risk of diabetes, hugely elevated over the general population risk perhaps, while vegans with the same genotype could even be at lower risk than the population average.  We rarely know enough about interacting or confounding variables, like other genes or lifestyles, relative to the one we know about (the tested genotype) to say more than what's average for that genotype.  But we have every reason to believe that not everyone with the genotype is at its average risk.

When risk differences are less than huge in absolute terms, personalized medicine cannot judge the relevance of these issues except at best in a here-and-now population context, such as by a case-controls study, and these exposure contexts are always changing.  That's why it's important to understand what probabilistic predictions mean, when it comes both to your golfing decisions, and to your life.

In fact for most diseases if you want to know much, much more about your risk than any genotype service can tell you,  just look at the health history of your relatives. That's been known since Darwin's time.  And unlike DTC services, that information's free!  No doctor bills, no unnecessary testing, no specific genes need to be identified.  If we learn of specific gene-based therapies, and you're at high familial risk, then it would be worthwhile to have a proper genetic counseling service do the test.

A Snake Oil factor, but it cuts both ways
The DTC business is cowboy capitalism at this stage, and selling this kind of snake oil to people totally unable to understand the actual meaning of the data is an ethical as well as policy issue, and of course there is disagreement about where the ethical lines are where they should be drawn.  Even most doctors--even most geneticists--are helpless to understand the nature, accuracy, or stability of these risks.  Of course there is always a lot of selling going on, as a glance at Parade or an airline magazine will clearly show (shrink your prostate!  get rid of age wrinkles! have a 20 year-old body at age 70!).  As P T Barnum said, there's a sucker sitting in every airplane seat.  But this is why regulation is important, in our view, in something so closely involved with life, death, and health-care costs.

We've suggested in our posts that the FDA should treat this kind of DTC 'advice' as practicing medicine, and license it only as a part of genetic counseling where it could in principle be properly constrained and regulated to stick closer to truths that we can generally agree on and that consumers (and counselors and physicians) can make reliable sense of.

However we must admit that this is partly a political stance by us.  If the entire business were just shifted to medical clinics, the same testing would probably take place, with the same level of understanding.  After all, the issues are complex even for those with sophisticated knowledge.

In fact, transferring the business (doubtlessly to be supplied, probably on a larger scale, by the same companies) and perhaps establishing it part of what would be lobbied into routine medical exams, the genomic testing could be much more costly to the health-care system, and more lucrative for the companies in the future, and hence perhaps even more problematic than it is now.  Still, we think regulation is better than caveat emptor.

Bottom line?
So the simple conclusion for us is that it's best to follow advice we've only known since Hippocrates a mere 2400 years ago (moderation in all things), and skip both that extra dessert and the personalized DTC genotyping.